CD147 is a highly glycosylated transmembrane protein that belongs to the immunoglobulin superfamily. CD147 is commonly over-expressed in many tumors (Li et al., 2009. HAb18G (CD147), a cancer-associated biomarker and its role in cancer detection. Histopathology 54, 677-687.), including carcinomas of liver, lung, breast, pancreas, prostate, and bladder. CD147 over expression level is correlated with tumor histopathologic type and clinical stage of disease. Importantly, CD147 surface expression is closely associated with tumorigenesis, tumor progression and reduced patient survival in various cancers, and these facts validate CD147 as a therapeutic target for cancer treatment.
Antibody Dependent Cell-mediated Cytotoxicity (ADCC) is a major clinical mechanism of action for therapeutic antibodies. Generally, when the antibody binds to a tumor target on the surface of a cell in a tumor tissue of a cancer patient, the Fc region of the antibody attracts effector cells, such as NK cells, by binding to the surface Fc receptor (e.g. CD16) of the NK cells. Binding of the Fc region to CD16 of the effector cells induces secretion of perforin and granzyme that lead to apoptosis of the target cells. Macrophages, neutrophils and eosinophils can also be activated by the Fc effector function.
ADCC efficacy of IgG antibodies is significantly dependent on Fc glycosylation patterns (Jefferis, 2009). We previously generated an anti-CD147 murine monoclonal antibody, HAb18 (U.S. Pat. No. 7,638,619, PCT/CN03/00188 and China patent No. ZL02114471.0), and developed a 131I-labeled HAb18 F(ab′)2 (named Licartin) to treat liver cancer (Xu et al., 2007a; A randomized controlled trial of Licartin for preventing hepatoma recurrence after liver transplantation. Hepatology 45, 269-276). Licartin has been shown to be effective in the treatment of liver cancer, demonstrating anti-CD147 antibodies as molecular targeted therapeutics. Although efficient, safe and tolerated in therapy, Licartin suffered from immunogenicity which triggers generation of human-anti-mouse antibodies (HAMA) in 4 out of 130 treated patients without affecting therapeutic results (Chen et al., 2006; Targeting radioimmunotherapy of hepatocellular carcinoma with iodine (131I) metuximab injection: clinical phase I/II trials. International journal of radiation oncology, biology, physics 65, 435-444.). Such limitations have prompted efforts to improve the efficacy and tolerability of HAb18 through antibody engineering, as well as the inconvenience of administration of a non-radioactively labelled therapeutic antibody. The present disclosure addresses these and other needs and provides several additional benefits for efficient and safe treatment of cancer patients, which will be described in the remainder of this document.